SUMMARY TRD3 will focus on the development and implementation of bioreactors for engineering clinically sized tissues and whole organs, with quantitative real-time imaging of biological processes, and determination of factors of disease remodeling of pathologic states in native whole organs. Specifically, we plan to develop two classes of next-generation bioreactor systems: (i) Visually guided bioreactors for lung regeneration by targeted cell replacement and bioactive agents; and (ii) Perfusion bioreactor for recapitulation of the post-myocardial infarct environment and study the modalities for regeneration of heart tissue. Our hypothesis is that this new class of imaging enabled bioreactors will provide considerable insights into the dynamic processes involved in tissue regeneration and thereby facilitate targeted interventions in complex tissues and whole organs. Two specific aims will be pursued. Aim 1 is to develop an integrated bioreactor-imaging system for functional regeneration of human donor lungs rejected as unacceptable for transplantation and to elucidate the factors associated with the determination of reversibility of the fibrotic process in diseased lungs. The bioreactor will allow interventions (such as removal and replacement of lung epithelium including associated exosomes) in targeted regions of the lung (from the upper airway all the way to alveolar spaces), with continuous non-invasive monitoring of the lung function during interventions and repair. Aim 2 is to develop a perfusion bioreactor system for heart tissue regeneration. The bioreactor will be designed to recapitulate the post infarct environment and investigate therapeutic modalities, with focus on cell-free treatment using exosomes secreted by therapeutic cells. An integrated controller will allow for the real time control of medium perfusion in response to measured metabolic parameters. Overall, the TRD3 projects aim to advance the field of tissue engineering by offering these unique bioreactor-imaging platforms to investigators as well as clinicians, and enabling them to obtain quantitative insights into the dynamics of growth and regeneration of tissues and organs to promote translational applications in lung transplantation and management of ischemic heart disease.